RU2002738C1 - Method of synthesis of n-hydroxyreas derivatives as r- or s-enantiometric forms or theirs mixture, or theirs pharmaceutically acceptable salts with alkaline metal - Google Patents

Abstract

Usage: in medicine, since the products have pharmacological activity. Essence: a method of obtaining new N-derivatives of urea of the General formula Ar-OAr1-Y-CH (CH bN (OH) (CONHR1). Where Ar - 3, 4-halogenated; Ar - 1.3-or 1,4-phenylene, Y - / E / - CH CH, R - hydroalkyl C-C in the form of R- or S-enantiomeric forms, or a mixture thereof, or their pharmaceutically acceptable salts with alkaline methanol Reagent V Ar-QAr - Y-CHfCH NHOH, where Ar, Ar1, Y have the above meanings. Reagent 2 alkali metal zincate. Reaction conditions in the solvent at 0 ° C in the presence of HCI.

Description

32002738 .4 The invention relates to new products of (a) 3- (4-Fluorophenoxy) toluene.

aqueous N-hydroxyurea general form-Solution of 4-fluorophenol (112.0 g, Aldrich)

lye anisole (250 ml) was added dropwise to

for 1 h to the stirred suspension

And OH5 NaH (26.4 g) in anisole (250 ml). When add d i 1. / (pouring was completed, the mixture was stirred

Ag-i-ag-y-y RLC at room temperature for 16 hours

ЈH-x UJNriKThen sequentially, for 30 minutes,

3-bromtoluene (188.1 g, Aldrich) was added,

where Ar is halogen-phenyl; 10 copper (I) chloride (50.0 g) and TDA-1 (tris (2- (2-meAg - 1,3- or 1,4-phenylene; toxethoxy (ethyl) amine in an amount of 158 ml

Y - (EJ-CH CH; When the addition was completed, the mixture on R1 means hydrogen or C1-C4-alkyl, was heated under reflux in the tevide of the R- or S-enantiomeric forms, or for 22 hours, then cooled to room temperature

mixtures, or their pharmaceutically accepted e-15 temperature, and was added to it (2000 ml)

mashy salts with alkali metal. I possess - ether. The mixture was filtered through Hyflo and

In order to inhibit the filtrate, they were washed with 2 M aqueous HO. 1M

5-lipoxypenase and antioxidant-derived NaOH and water, then dried and with long-term exposure. They were evaporated in vacuo. The remaining oil of the indicated compounds can find 20 distilled and the desired product is obtained (101.9

use in prophylaxis or treatment d) with T. boil. 129-134 ° C (9 mmHg).

clinical diseases in which- (o) 1-Dibromomethyl-3- (4-fluorophenocazane is a metabolic inhibitor of si) benzene.

arachidonic acid, mediated by a solution of the product from stage (a) (101.9 g)

swarm is migoxygenase. 25 and NBS (206.7 g) in CCU (500 ml) was heated to

Derivatives of the hydroxamic boiling point with the reverse chill acid are α-alkylated with N-alkanoyl. Then, AIBN (100 mg) and hydroxamic acids (0- which is the mixture) were subjected to irradiation with a medium lamp with inhibitors of 5-lipoxygenase pressure at 254 nm when heated from the Enzyme. The disadvantage is unstable 30 reflux for 7 h. R-isomer coavailability. As a result, only pure portions of AIBN were added, it was necessary to use only pure portions of AIBN. The mixture was cooled to the S-isomer, which reduces the cost-effectiveness of room temperature, filtered and using. The filtrate was evaporated in vacuo to give spruce present invention is left 35 as an orange oil proizvol- a method for producing (195.3 g).

N-hydroxyureas of the general formula 1 (c) 3- {4-Fluorophenoxy) benzaldehyde.

or pharmaceutically acceptable salts thereof A mixture of the product from step (b) (181.8 g)

with an alkali metal in the form of R- or S-eian- CaCO3 (151.7 g) and EDTA 2Na -2NgO (37.7 g) in thiomeric forms, or mixtures thereof, I enclose 40 ethanol / water mixtures (1140 ml / 284 ml) heated in that the compound was refluxed for 20 hours. The mixture was cooled to room temperature, filtered and the filtrate was evaporated 1 in vacuo. The remaining oil was taken in

Ar-0-Ar-Y-C-NHOHSh)} 45 ether (500 ml), washed with 2M aqueous HCI solution, saturated aqueous NaHCOa solution and water, dried and evaporated

where Ar, Ar1 have the above meanings, in a vacuum, yielding a viscous orange oil, they are reacted with cyanogen, which was subjected to chromatography with a double volume of alkali metal under conditions, providing 50 through silica gel using mixtures that convert the NA group to ether (40 -60 ° C) of petroleum ether (1: 9), -CONHR group, followed by obtaining the desired product (69.6 g), if necessary, by converting the form- (d) CZ- (4-Fluorophenoxy) phenyl compound but-1-enmules 1 in an alkali metal salt. 3-one.

55 A mixture of the product from step (c) (69.6 g),

The invention is illustrated by dimethylacetylmethylphosphonate (56.2 g) and

examples below. Anhydrous CaCO3 (88.9 g) in THF (500 ml)

Example 1. The preparation of (E) -N- {3- 3- {4- was refluxed in tefluorophenoxy) phenyl} -1 (Y, 5) methylprop-2 for 24 hours. The mixture was cooled to room temperature.

n-1-yl-M-hydroxyurea. temperature, filtered and the filtrate was evaporated in vacuo. The remaining oil was taken up in ether (500 ml) and washed in vacuo. The remaining oil was taken up in ether (500 M3i), washed with water, a saturated aqueous MAHCO3 solution and water, dried and evaporated in vacuo to give the desired product (83.4 g).

(e) M- {1- 3- (4-Fluorophenoxy) phenyl but-2-en-3-yl-hydroxylamine.

Pyridine (63.6 g) was added dropwise over 1 hour to a stirred solution of the product from step (d) (82.5 g) and hydroxylamine hydrochloride (33.6 g) in methanol (1000 ml). When the addition was complete, the mixture was stirred for 1.5 hours, then cooled in ice / water and anhydrous oxalic acid (289.8 g) was added. Methanol (750 ml) was added and sodium pyanoborohydride (101.2 g) was added to the stirred mixture over 3.5 hours. When the addition was completed, the mixture was stirred for 2 hours at 0-5 ° C. and then for 20 hours at room temperature. The mixture was filtered, the filtrate was evaporated in vacuo and the remaining oil was taken up in ether (1000 ml), washed with water and cooled with ice / water. By adding a JM aqueous NaOH solution, the pH of the mixture was adjusted to about 9 and the organic phase was removed. The aqueous phase was extracted with ether and the organic phase and the extract were combined, washed with water, dried and evaporated in vacuo to give the desired product as a tan oil (92.7 g), which crystallized upon standing.

(f) (E) -M- {3- 3- (4-fluorophenoxy) phenylZ-1 (P, 5) methylprop-2-en-1-yl} -M-hydroxy

chevina. - A 2M aqueous HCI solution (645 ml) was added at 0 ° C. over 1.5 h to a stirred solution of the product from step (e) (88.0 g) and potassium cyanate (79.2 g) in THF (750 ml) ) When the addition was completed, the mixture was stirred at 0 ° C for 2 hours, then allowed to separate. The organic phase was removed, the aqueous phase was extracted with ether, and the organic phase and the extracts were combined, washed with a saturated aqueous MAHCO3 solution and water, dried and evaporated in vacuo to give a colorless, sticky solid. The latter was triturated with a mixture of ether (40-60 petroleum ether (3: 2), then recrystallized from a mixture of ethyl acetate (40-60 ° С) petroleum ether (2: 1), giving a colorless verde substance (67.8 g) s mp 133.5-135 ° C decomp.).

Analysis: C 64.81%; 64.55%; H 5.43%,, 42%, N8.52%; 8.66%.

Example 2. Obtaining (E) -N- {3- {3- {4-fluorophenoxy) phenyl} -1 (Named prop-2-en-1-yl} -M-hydroxyurea,

(a) But-3-in-2- (5) -ol.

5 But-3-in-2 (I) -ol was obtained using

decomposition into constituents of (±) -but-3-yn-2-ol (Albrich) in accordance with the procedure described in J. Med. Chem. 31,156.1988, (c) M, 0-bis (tert-butoxycarbonyl) -M10 but-3-in-2 (P) -yl hydroxylamine.

DEAD (180.0 g) was added dropwise at (-) 78 ° C over 1 h to a stirred solution of but-3-yn-2- (Я} -ol from step (a) (55.0 J) triphenylfesfin (258.0 g) ) and N, 015 bifret-butoxycarboxyl) hydroxylamines (183.0 g, Fluka) in toluene (1500 ml). When the addition was completed, the mixture was allowed to warm to room temperature and then it was stirred for

0 2 hours. Petroleum ether (1500 ml) was added to the mixture (40-60 ° C), the mixture was filtered through a Hyflo filter and the filtrate was evaporated in vacuo to give the desired product & a form of oil that crystallized upon standing.

5 (c) M, O-bis (tert-butoxycarboxide) -M-but-3-en-2 (I) -yl hydroxyssilamine.

A stirred mixture of the product from step (b) (200.0 g) and a 5% weight / mass solution Pd / 8aS04 (8.8 g) in pyridine (1000

0 ml) was hydrogenated at atmospheric pressure until the absorption of hydrogen ceased. The mixture was filtered. Through a Hyflo filter, the filtrate was evaporated in vacuo and the remaining oil

5 were taken in ether (1000 ml), washed on May 20. % aqueous solution of citric acid and water, dried and evaporated in vacuo, according to the target product (192.0 g).

(d) 1-bromo-3- {4-fluorophenoxy) benzene.

An aqueous KOH solution (49.0 g in 100 ml of water) was added to a stirred solution of 4-fluorophenol (84.0 g in methanol (250 ml). When the addition was completed, the mixture was evaporated in vacuo and the remaining solid

5, the substance was triturated and taken into 1-methyl-2-pyrrolidinone (300 ml). To the mixture was added 3-ftsrbromobenzene (131.3 g, Albrtch) and the mixture was heated under reflux for 24 hours, then cooled to room temperature.

0 temperature, poured into water (1500 ml) and was extracted with ether. The combined extracts were washed with 2TI aqueous NaOH, 2M aqueous HCI and water, dried and evaporated in vacuo. The oil remaining for 5 s was distilled to obtain the desired product (103.0 g) with boiling point. 85-100 ° C (0.25 mm Hg).

(e) (E) -M- {3- 3- (4-fluorophenoxy) phenyl-1 (Y) -methylprop-2-en-1-yl} hydroxylamine.

A mixture of the product from step (c) (100.7 g), the product from step (d) (103.0 g) tri (o-tolyl) phosphine (10.0 g) and palladium (II) acetate (4, 0 g) in tri (n-butyl) amine (300 ml) was stirred at 115 ° C for 3 hours. The mixture was cooled to about 90 ° C, evaporated in vacuo and the residue was taken up in ether (1000 ml), washed with 33 wt. % aqueous citric acid solution and filtered through a Hyflo filter. The filtrate was washed with a 10 wt.% Aqueous citric acid solution and dried with water and evaporated in vacuo to give a viscous tan oil. The latter was taken in methanol (1000 ml) and conc. HC (100 ml) and the mixture were heated under reflux for 1 hour, then cooled to room temperature and evaporated in vacuo. The residue was taken up in water (1000 ml) and a YuM aqueous NaOH solution (125 ml), extracted with ether and the combined extracts were washed with water, dried and evaporated in vacuo. The remaining tan oil was chromatographed over silica gel using a mixture of ether (40-60 ° C) petroleum ether (9: 1) followed by ether to give the desired product as a yellow oil (21.9 g).

(f) (E) -M- {3- {3- {4-fluorophenoxy) phenyl-1 {p {) -methylprop-2-en-1-yl} -M-hydroxy-wine.

 A 2M aqueous HCI solution (160 ml) was added dropwise at 0 ° C. over 1 h to a stirred solution of the product from step (e) (21.9 g) and potassium cyanate (19.7 g) in THF (190 ml) ) When the addition was complete, the mixture was stirred at 0 ° C for 1.5 hours, then a saturated aqueous solution of NaCI was added to the mixture, and the organic phase was removed. The aqueous phase was extracted with ether and the organic phase and the extracts were combined, washed with 2M aqueous HC, saturated aqueous MAHCO3, water and saturated aqueous NaCI, dried and evaporated in vacuo to give a siliceous solid, which was recrystallized from ethyl acetate (40-60 ° C). C) petroleum ether (2: 1), obtaining colorless plates (17.7 g) with a mp. 133-135 ° C (decomp.) 200 MHz H NMR and IR were consistent with the target product.

Analysis: C 64.10%; 64.54%; H 5.47%;

5.42: N8.78%, 8.86%. C and L3 ± 40.81 ° (s-1.0, UNN).

Example 3. Obtaining (E} -M- {3- {3- {4-fluorophenoxy) phenyl -1 (5) -methylprop-2-en-1-and n} -N-r idroxyurea.

(A) But-3-in-2 (q;) - ol.

But-3-yn-2 (P) -ol was prepared by decomposition into (±) but-3-yn-2-ol (Aldrlch) in accordance with the procedure described in J. Med. Chem. 31,156, 1988.

(6) M, 0-bis (tert-butoxycarbonyl) -Y (but-3-in-2 {5) -yl) hydroxylamine.

DEAD (81.8 g) was added dropwise at (-) 70 ° C over 1 h to a stirred solution of but-3-in-2 (I) -ol from step (a) (25.0

0 g), triphenylphosphine (117.0 g) and M, 0- (bis) - tert- (butoxycarbonyl) hydroxylamine (83.2 g Fluka) in toluene (760 ml). When the addition was complete, the mixture was allowed to warm to room temperature.

5 temperature, then filtered and the filtrate was evaporated in vacuo. The remaining oil was purified by chromatography twice through silica gel using DCM and a mixture of ether (40-60 ° C) petroleum

0 ether (1: 4), respectively, obtaining the desired product as a pale yellow oil (98.6

d).

(c) M, O-bis (tert-butoxycarbonyl) -M- (but-3-en-2 (5) -yl) hydroxylamine.

5 A stirred mixture of the product from step (b) (98.6 g) and a 10% weight / mass solution of Pd / BaS04 in pyridine (500 ml) was hydrogenated at atmospheric pressure until hydrogen

0 ceased to be absorbed. The mixture was filtered through a Hyflo filter, the filtrate was evaporated in vacuo and the remaining oil was taken up in ether (500 ml), washed on May 20. % aqueous citric acid solution and water, dried5 and evaporated in vacuo to give the desired product as a pale orange oil (90.0 g).

(d) 1-Bromo-3- (4-fluorophenoxy) benzene. 1-Bromo-3- (4-fluorophenoxy) benzene was prepared according to the method described in step (d) of synthesis example 2.

(e) (E) -M- {3- 3- (4-fluorophenoxy) phenyl - 1 (5) methylprop-2-en-1-yl} -hydroxylamine,

A mixture of the product from step (c) (57.4 g) of the product from step (d) (58.7 g), tri (O-tolyl) phosphine (5.0 g) and palladium (I) acetate (2.0 g) in tri (n-butyl) amine (150 ml) was stirred at 110-120 ° C for 3.5 hours. The mixture was cooled to room temperature, evaporated 0 in vacuo and the residue taken up in ether (500 ml) and filtered through a Gifto filter. The filtrate was washed with a 10 wt.% Volume of an aqueous solution of citric acid and water, dried and evaporated in vacuo to give a red-5 cotton-brown oil. The latter was taken up in methanol (500 ml) and HCI (50 ml) and the mixture was heated under reflux for 1 h, then cooled to room temperature and evaporated in vacuo. The residue was taken up in water (500 ml) and a 10 M aqueous NaOH solution

(60 ml) was extracted with ether and the combined extracts were washed until neutral with water, dried and evaporated in vacuo. The residue was flash chromatographed over silica gel using a mixture of ether (40-60 ° C.) of petroleum ether (1-1). discarded, then the mixture was used in a ratio of 9: 1), whereby the desired product was obtained as a viscous pale yellow oil (32.5 g).

(f) {E) -M- {3- {4-fluorophenoxy (phenyl} -1 (5} - methylprop-2-en-1-yl} -G-hydroxyurea.

A 2M aqueous hydrochloric acid solution (71.1 ml) was added dropwise at 0 ° C. over 45 minutes to a stirred solution of the product from step (e) (32.5 g) and potassium cyanate (29.3 g) in tetrahydrofuran (282 ml). Upon completion of the addition, the mixture was stirred at 0 ° C for 45 minutes, then a saturated aqueous NaCI solution was added and the organic phase was removed. The aqueous phase was extracted with ether and the organic phase and the extract were combined, washed with a 2M aqueous solution of HC1 and water, dried and evaporated in vacuo to give a sticky solid, which was recrystallized from ethyl acetate, to give colorless plates (25.8 g) with mp 131-132. 200 MHz 1H, NMR and IR are identified with the desired product.

Analysis: C 64.7%; 64.54%; H 5.42%, 5.52%; N8.79%; 8.86%.

.61 ° (s-1.0; JUN).

Example 4. Preparation of (E) -N- {3- {3-

(4-chlorophenoxyl) phenyl -1 ($) methylprop-2-en-1-yl} -M-hydroxyurea.

(a) (4E) (4-chlorophenoxy) phenyl buten-3-one 10N. an aqueous solution of MaOH (2 ml) was added to a solution of 3- (4-chlorophenoxy) benzaldehyde (23.3 r) Aldrich in acetone (150 ml), and the mixture was vigorously stirred. After several minutes of stirring, the temperature was raised to 32 ° C. The mixture was allowed to stand for 5 minutes and then an R 2M aqueous hydrochloric acid solution (600 ml) was poured and extracted with a mixture of ether and petroleum ether (1: 1, 400 ml). The extract was washed with water and a saturated aqueous solution of MaOH was dried over magnesium sulfate and stripped to give the aldol product. The latter was taken up in toluene (300 ml), p-toluenesulfonic acid (1 g) was added and the mixture was heated for 1 h. The mixture was then cooled, washed with saturated aqueous sodium bicarbonate and saturated aqueous NaCI, dried over sulfate magnesi and desorbed. The residue was eluted through a silica gel column using a mixture of methylene chloride (40-60 ° C) petroleum ether (1: 1, followed by a ratio change of 3: 1), and the eluate was desorbed to give the desired product (19.0 g).

(o) (E} -1- (3- (4-chlorophenoxy) phenylbuten-3-onoxime.

The product of step (a) (19.0 g) and hydroxylamine hydrochloride (6.9 g) were taken up in methanol (100 ml), pyridine (200 ml) was added and the mixture was stirred for 1 h. The mixture was then absorbed, redissolved in ether (200 ml), it was washed with 2M aqueous hydrochloric acid and saturated aqueous NaCl. dried over magnesium sulfate and stripped to give the desired product (20.3 g),

(c) (E) -M- {1-methyl 3- 3- (4-chlorophenoxy) phenyl} prop-2-enyl} hydroxylamine.

The product from step (b) (20 g) was taken up in methanol (100 ml) and oxalic acid (31.3 g) was added. The mixture was cooled in an ice bath and sodium cyanoborohydride (22 g) was added portionwise under a nitrogen atmosphere for 3 hours. The mixture was stirred for 1.5 hours, then additional sodium cyanoborohydride (2 g) was added and stirring was continued. for 0.5 hours. The mixture was then stripped and the residue partitioned between ethyl acetate (300 ml) and water (300 ml). The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous NaD, then desorbed to give the desired product as crude hydroxylsmin.

(d) (E) g- {1-methyl-3- 3- (4-chlorophenoxy) phenyl prop-2-en-T-yl} -hydroxyblocker.

A portion of the product from step (c) (6.0 g) was taken in THF (60 ml) and potassium cyanate (4.9 g) was added at 0 ° C. After 15 minutes, a 5M aqueous HCI solution (20 ml) was added dropwise and the mixture was stirred for 10 minutes. Then, a saturated aqueous solution of NaCI (100 ml) and ether (100 ml) were added to the mixture, and the organic layer was separated, washed with a 2M aqueous solution of HCl (100 ml) and a saturated aqueous solution of NaCI (100 ml), dried over MgS04 and subjected to desorption yielding the desired product that recrystallized from an ethyl acetate / petroleum ether mixture. Yield 4.4 g; mp. 132-135 ° C.

Example 5. Obtaining (E) -N- {3- 3- (4-chlorophenoxy) phenyl -1- {5} -methylprop-2-en-1-yl} -hydroxyurea.

(a) ((4-chlorophenoxy} phenyl but-1-en-3-one.

A mixture of 3- (4-chlorophenoxy) benzaldehyde (50.0 g, Aid rich) dimethylacetylphosphonate (35.7 g, Lancaster) and anhydrous K2CO3 (59.4 g) in THF (300 ml) was stirred in an atmosphere of H2 at 55-55 ° C for 20 hours. The cooled mixture was filtered, the residue was washed with THF, and the combined filtrates were evaporated in vacuo to give an orange oil, which was subjected to flash chromatography on a silica gel column using an ether mixture (40-60 ° C, petroleum ether) 1: 1 by volume as eluent, to give the desired product as a viscous pale yellow oil (52.8 g).

(b) (E) -1 (K) methyl-3- 3- (4-chlorophenoxy) phenol prop-2-en-1-ol.

BH3 THF (1.0 M, 96 ml) and a solution of the product from step (a) (52.7 g) in THF (total volume 96 ml) were simultaneously added in a nitrogen atmosphere to the stirred solution (8) -3.3- diphenyl-pyrrolo (1,2-cX1,3,2) oxazab orilidine in THF (0.3 M, 33 ml, prepared according to the method described in LC 53.2861 (1988)). When the addition was complete, the mixture was stirred at room temperature for 15 minutes, then ice (2 M aqueous HC1 300 g / 300 ml) was poured into the mixture, stirred for 30 minutes and extracted with ether (3x300 ml). The combined extracts were washed with a 2 M aqueous HC solution (200 ml), saturated aqueous TSOPOM MaHCO3 (200 ml) and water (200 ml), dried over N82S04 and evaporated in vacuo to give the desired product as a viscous yellow oil ( 55.3 g), which was partially crystallized from a mixture of ether (40-60 ° С, petroleum ether (1: 1) by volume). The mother liquor was decanted and flash chromatographed on a silica gel column to give the desired product as

pale yellow oil (25.7 g), and & 3 5 + 8.7 ° (, 0, UNN). 200 MHz 1H, NMR and W are consistent with the proposed structure.

(c) (E) -MO-bis (tert-butoxycarbonyl) - N - {1 (3) -methyl l-3- 3- {4-chlorophe n o xi) phen and l J-prop-2-ene -1-yl} hydroxylamine.

A solution of DEAD (24.5 g) in toluene (50 ml) was added to the stirred product mixture from step (b) (25.7 g) M, 0-bis {tert-butoxycarbonyl) hydroxylamine (22.9 g, Fiuka) and triphenylphosphine (36.8 g) in toluene (375 ml) at (-) 65 - {-) 700C. When the addition was complete, the mixture was stirred for 4 hours at (-) 65 - (-} 700C. Then triphenylphosphine (5.0 g) was additionally added followed by further addition of DEAD (3.3 g) and the mixture was stirred for another 1 h at (-) 65 - {-} 700 ° C. The heated mixture was evaporated in vacuo to give a brown oil, which followed

0

5

0 5 0 5 0

5

5

but subjected to flash chromatography through two silica gel columns using DCM and a mixture of DCM (petroleum ether) ether (3: 6: 0.25 v / v / v), respectively, as eluents. giving the desired product as a viscous yellow oil (20.3 g).

(d) (E) -M-1 (5) -methyl-3- 3- {4-chlorophenoxy) phenyl prop-2-en-1-yl} hydroxylamine.

Tri Toruxus acid (28 ml) was added in an N2 atmosphere at 0 ° C to a stirred solution of the product from step (c) 20.3 g in DSM (112 ml). When the addition was completed, the mixture was stirred at room temperature for 3 hours, then ether (100 ml) and water (100 μl at 0 ° C were added to the vigorously stirred mixture; an aqueous solution of JM NaOH {32 ml) was added. The mixture was made basic with excess saturated aqueous NaHCOa, extracted with ether (200 ml) and the extract was washed with saturated aqueous MAHCO3 (100 ml and water (2x100 ml), dried over N32S04 and evaporated in vacuo to give a viscous yellow oil which was flash chromatographed on silica gel column using an ether / petroleum ether mixture (4: 1), after which the desired product was obtained, mp 83-84 ° С (а) 25-31.1 ° (с ± 1.2; СНС1з) .

(e) (E) -M- {1- (5) -methyl-3- 3- {4-chlorophenoxy) phenyl lrop-2-en-1-yl} -M-hydroxymethine.

Portions of the product from step (d) (0.29 g) were taken in THF (10 ml) and potassium cyanate (0.25 g) was added at 0 ° C. After K min, a 2M aqueous HCI solution was added dropwise and the mixture was stirred for 2 hours. Then, saturated aqueous NaCI solution (50 ml) and ether (50 ml) were added to the mixture, and the organic layer was separated, washed with a saturated aqueous solution. NaHCOs (50 ml) were dried over MgS04 and stripped to give the desired product, which was recrystallized from ethyl acetate / petroleum ether. Yield 0.26 g: mp. 119-120 ° С, ap3 -40.0 ° (, 0; ЕУН).

Example 6, Preparation of the (E) -g4- {3- 3- (4-fluorophenoxy) phenyl 1 - (R, 5} -methylprop-2-en-1-yl} -M-hydroxyurea sodium salt.

The compounds of Synthesis Example 1 (1.0 g) were dissolved in a mixture of aqueous sodium hydroxide (0.11 g in 25 ml of water) and methanol (30 ml). The methanol was evaporated in vacuo and the remaining solution was freeze dried to give the desired product as a cream solid.

200 MHz TH NMR (DMSO-de, ppm): 1.10-1.21 (ZI, d, - СН3), 4.75-4.92 (14, m, СН- /,

5.27-6.14 (2H, br.s. NH2), 6.22-6.51 (2H, s., NOSI) and 6.69-7.37) (9H, m. Aromatics), absence - OH signal.

Examples of pharmaceutical formulations.

The active ingredient in the following formulations is any compound of the invention (as defined above, for example, any of the compounds of Synthesis Examples 1 to 5).

Example A. Composition of the tablet, mg:

Active

ingredient 5.0

Lactose82.0

Starch 10.0

Povidone 2.0

Magnesium Stearate 1.0

Mixed have the active ingredient, lactose and starch. The powders are granulated using a solution of povidone in purified water. The granules are dried, magnesium stearate is added and compressed to form tablets (100 mg per tablet).

Example B: Composition of ointment:

Active

ingredient mg 1.0

White soft

paraffin, gdo 100.0

The active ingredient is dispersed in a small volume of carrier. Gradually introduce it into the mass to obtain a smooth, homogeneous product. Crumpled metal tubes are filled.

Example C. Cream for local use, g:

Active

ingredient1.0

Polavax 20.0

Anhydrous

lanolin 2.0

White bee

wax 2.5

Methylhydroxybenzoate0.1

Distilled

water Up to 100.0

Heated polavax, beeswax and lanolin together at 60 ° C. A solution of methylhydroxybenzoate is added. Homogenize using high speed mixing. The temperature is allowed to drop to 50 ° C. The active ingredient is added and dispersed. It is allowed to cool with stirring at a slow speed.

Example D. Lotion for local use, g:

Active ingredient1.0

Sorbitan monolaurate 0.6

Polysorbzt 200.6

Ketostearyl

alcohol 1.2

Glycerin 6.0

Methylhydroxy-5-benzoate 0.2

Purified water

B.P., mlUp to 100.0

Methylhydroxybenzoate and glycerol were dissolved in 70 ml of water at 75 ° C. Sorbitan 10 monoleurate, Polysorbate 20 keto-stearyl alcohol were melted together at 75 ° C and added to the aqueous solution. The resulting emulsion was homogenized, allowed to cool with 15 continuous stirring, and the active ingredient was added as a suspension and the remaining water. The mixture was stirred until it became homogeneous. 0 PRI me R E. Eye drops, g:

Active

ingredient0.5

Methylhydroxybenzoate0.01 5 Propylhydroxybenzoate0.04

Purified water

B.P., mlUp to 100.0

Methyl and propylhydroxybenzoates were dissolved in 70 ml of purified water at 75 ° C and the resulting solution was allowed to cool. The active ingredient was then added and the solution was made up to 100 ml with purified water. The solution was sterilized 5 by filtration through a 0.22 µm membrane filter and aseptically filled into suitable sterile containers.

Example D. Inecious solution: O Active

ingredient, mg 10.0 mg

Water for injection

B.P., mlUp to 1.0

The active ingredient was dissolved in half the amount of water for injection and then the solution was made up to volume and sterilized by filtration. The resulting solution was distributed in ampoules under aseptic conditions. 0 Example C. Capsules with powder for inhalation, mg:

Active ingredient

(powder 0.5-7.0-msh) 4.0

Lactose (powder 5 30-90 microns) 46.0

The powders were mixed until they became homogeneous and filled into capsules of suitable size from hard gelatin (50 mg per capsule).

Example I. Inhalation aerosol, Mr- Active ingredient (0.5-7.0 μm)

powder200

Sorbitan

trioleate100

Saccharin Sodium

(powder 0.5-7.0 μm) 5

Methanol2

Trichlorofluoromethane, g 4.2

Dichlorodifluoromethane, ml Up to 100

Sorbitan trioleate and menthol were dissolved in trichlorofluoromethane. Sodium saccharin and the active ingredient were dispersed in a mixture, which was then placed in suitable aerosol cans and dichlorofluoromethane was passed through a valve system. This composition contained 2 mg of active ingredient for every 100 µl of dose.

Biological data.

Ex vivo inhibition of 5-lipoxygenase.

A preliminary study in rats and rabbits showed that the racemate of synthesis example 1 and the corresponding enantiomers of synthesis examples 2 and 3 effectively inhibit the stimulated synthesis of leukotriene B4 (LTB4), a compound formed by mz arachidonic acid via 5-lipoxygenase.

After administration of the test compound in plasma, the concentration of LTB4 was periodically measured and expressed as a percentage of the average control value. The procedure used is described in J. Pharmaa 94,528 (1988) and can be briefly described as follows.

After 2 minutes of collection, repeated samples (0.5 ml) of blood were stimulated with A23187 calcium ionophore (final concentration 15 µg / ml) for 30 minutes at 37 ° C. When incubation was completed, the samples were centrifuged (12K, / ° C for 2 minutes) and the cell-free plasma was removed. Then, using a special radio-immunoassay, the plasma concentration of LTB4 was determined.

The compounds of Synthesis Examples 1-3 all inhibited in vivo-stimulated LJB4 synthesis for several hours after their administration. The compound of Synthesis Example 1, for example, when it was administered orally to rabbits at a dose of 2 mg / kg, inhibited LTB4 synthesis by more than 50%. for a period of more than 16 hours. The same compound, when administered orally to rats at a dose of 10 mg / kg, inhibited LTB4 synthesis by more than 50% for more than 10 hours. The enantiomers of synthesis examples 2 and 3 gave similar results.

Inhibition of 5-lipoxygenase in vitro.

Blood from ordinary aspirin-free volunteers was centrifuged to separate white blood cells from red blood cells and platelets. A solution of the test compound in DMSO (10 µl, a final concentration in the range of 0.01-100 µM) was added to the crate homogenate (470 µl), and the mixture was incubated at 37 ° C for 5 minutes. Then, solutions of arachidonic acid in methanol were added simultaneously.

5 (250 µM, 10 µM, final concentration 5 µM) and calcium chloride in water (100 mM, 10 µL, final concentration 2 mM), and the mixture was incubated at 37 ° C for another 5 minutes. The reaction was stopped using

0 bales. Conducted radioimmunoassay for leukotriene B4.

The experiment was repeated using whole human blood stimulated by an ionophore.

5 For the compounds of Synthesis Examples 1-5, the results are shown in Table 1 (ICso, µM).

Antioxidant activity.

As a measure of antioxidant activity, the ability of the compounds of the invention to capture the peroxyl radical was determined by testing the ability of each compound to inhibit peroxylelenylinolenic acid using the method described in Blochem. Pharm. 38, 1465 (1989).

The compound of Synthesis Example 1 had an apparent rate constant (Cd) of peroxyl radical uptake of 0.408.

0 Effects of combination with MZADD.

Male New Zealand white rabbits (2.5-3 kg) were immunized with intradermal injections of 4 mg ovalbumins in 1 ml of complete Freunda adjuvant. After 14

5 days the animals were re-immunized in the same way. 5 days after the second immunization, arthritis was induced in the right knee joint by injecting 1 ml of sterile solution of oval-bumin (5 mg / ml) into the joint cavity.

and

The joint diameters (on a randomized blind basis) were measured with a compass at frequent intervals after provocative administration of antigen 5. After 14 days, the animals were sacrificed and the articular space was washed with 1 ml of physiological saline and the resulting fluid was taken for total and differential count of leukocytes.

Sensitized animals were randomly assigned to groups 5-8. The compound according to the synthesis example ° 1: (E) -M- {1-methyl-3- {3- (4-fluorophenoxy) phenylprop-2-en-1-yl} -M-hydroxyurea (compound A), was introduced in suspension after 18 hours of grinding in a ball mill in 0.25% celacol, and as a carrier, the non-steroidal anti-inflammatory indomethacin was dissolved in a small volume of 1M Tris buffer with pH 8. and then brought to the desired volume of 0.25% - tselakolom. Control animals received 0.25% celacol. Each animal received an oral dose (approximately 5 ml) of the vehicle or drug 3 times every 24 hours. Doses were given at 8.0 a.m., 4.0 p.m. and 12 p.m. for 16-17 days, starting from 1 hour before administration of antigen on day zero. All doses were given orally with a gastric tube. The groups were as follows:

1-7: control (5 ml 0.2 &% - whole cell, x 3/24 h)

8-14: 1 mg / kg indomethacin dissolved in 0.25% celacol x 3/24 h

15-21: 2 mg / kg of compound A suspended in 0.25% coelacola x 3/24 h

22-28: 2 mg / kg of compound A suspended in 0.25% celacol plus 1 mg / kg of indomethacin dissolved in 0.25% celacol.

Joint swelling

In control animals, antigen administration caused an increase in joint diameter of 6-7 mm, which peaked 2 days after administration of a provocative dose of antigen. Joint swelling remained in the control group during the experiment period (14 days) and by the time the animals were killed, the diameters of the arthritic joints were approximately 5 mm larger. Treatment with none of the drugs reduced joint swelling during the first two days after the release of a provocative dose of the substance, but, starting from the third day onwards, compound A reduced swelling by up to 26% and indomethacin by 53%, compared to control animals processed by the carrier. The largest and most consistent decrease in swelling (up to 72%) was observed in the group receiving the combination of compound A and indomethacin. The results are shown in table.2.

The study of synovial fluid.

The synovial and lining tissue was removed from the joint, fixed, treated, cut and stained for examination under a microscope. Histological indices were derived for the total mass of the inflamed synovial prosthesis, lymphocyte infiltration, and polymorphic contents. Microscopic specimens on 5 glass slides were examined on a randomized, blind basis.

Synovial fluids from arthritic joints of control animals contained approximately 106 leukocytes, of which 0 approximately 80% were polymorphs. Compound A or indomethacin alone both slightly reduced the mean leukocyte infiltrate in the synovial fluid, but the greatest decrease was 5 as a result of using compound A with indomethacin. The number of leukocytes (cell number xY6) is presented below.

Compound A Indomethacin A + Indomethacin Control

0 6.17.30.97.9

Assay of Cartilage Proteoglycan The connective cartilage was opened from the ends of the femur and digested with popain before measuring the concentration of 5 sulfonated glycosaminoglycans (CaSov). The proteoglycan content was expressed in μg CAC / mg wet cartilage mass and compared with values obtained in the case of cartilage from the opposite control joint.

The connective cartilage dissected from the arthritic joints of the animals treated with the vehicle, 14 days after the administration of a provocative dose of antigen, 5 contained 43% less proteoglycan than the cartilage from the opposite joints of the same animals.

Compound A or indomethacin alone reduced both proteoglycan losses from 0 cartilage, but the greatest decrease was in the group receiving both compound A. and indomethacin. The results are shown below, Loss of proteoglycan. % Compound A Indomethacin A + Indome- 5 tacin Control

34382643

Histological evaluation of synovial lining

In the synovial lining of a group of animals receiving both compound A and

indomethacin, the number of both lymphocytes and

total cells decreased significantly.

The results are shown in table 3.

5 The above data demonstrate the cytoprotective effect of Compound A in arthritis, especially in the presence of the non-steroidal anti-inflammatory drug indomethacin.

Toxicity data

The compound of Synthesis Example 1 was administered to mice orally at doses up to 300 Ig / kg and intraperitoneally at doses up to 100 mg / kg. There were no deaths or serious adverse effects.

The advantage of the obtained compounds is that (the KNurma enantiomer of known hydroxamates decomposes faster than the (3) form, while in the case of enantiomers of the N-hydroxyurea derivatives of formula 1 of the present invention and the (R) - and {$) - form extended life.

An increase in the stability of the (I) -enantiomer leads to an economic effect resulting from the ability to obtain not an individual enantiomer and use not an individual enantiomer, but a racemate that contains 50% of the reactive enantiomer.

The compound of formula I is a low toxicity group.

(56) EP No. 0299761, cl. C 07 C 259/06, 1979.

Joint swelling / mm /

Table 1

table 2

Table 3

Claims (1)

The claims A method of obtaining derivatives of M-hydroxyureas of the General formula I H5 | HE Ar-OAr -Y-C-N7 CH3 CONHR where Ar is 4-halo phenyl; W Ar is 1,3-or 1,4-phenylene; Y- (E) -CH-CH; R is hydrogen or Ct is O-alkyl: in the form of R- or S-enantiomeric forms or fifteen mixtures thereof, or their pharmaceutical administration alkali metal salts, characterized in that the compound is a common N Formulas II Ar — O — Ar — Y — C — NHOH I SNZ where Ar, Ar, Y have the indicated meanings, are reacted with an alkali metal cyanate under conditions providing for the formation of the CONHR1 group. where R has the indicated meanings, followed by. JIOH, by conversion of the compound of Formula I to an alkali metal salt.